There are over 200 different known cancers that afflict human beings. Cancer causes millions of deaths a year worldwide and rates are also rising as more people live to an older age and urbanization causes more stress. It is anticipated that one in eight people currently alive will eventually die of cancer. Cancer manifests itself in a wide variety of forms, characterized by different degrees of invasiveness and aggressiveness. Malignant tumors are the second leading cause of death in the United States, after heart disease.
Cachexia is a positive risk factor for death, meaning that if a patient has cachexia, the chance of death from the underlying condition is increased dramatically. Skeletal muscle atrophy is a nearly universal consequence of cancer. Cachexia is considered the immediate cause of death of a large proportion of cancer patients, ranging from 22% to 40% of cancer patients. The pathogenesis of cancer cachexia is poorly understood. It is believed that multiple biologic pathways are involved, including proinflammatory cytokines and tumor-specific factors such as proteolysis-inducing factor. Muscle atrophy is believed to occur by a change in the normal balance between protein synthesis and protein degradation. During atrophy, there is a down-regulation of protein synthesis pathways and an activation of protein breakdown pathways. Only limited treatment options exist for patients with clinical cancer cachexia. Current treatment strategies involve attempting to improve an individual's appetite using appetite stimulants and protein supplementation to provide the individual with required nutrients.
The reversal of cancer cachexia and muscle wasting leads to prolonged survival, and with the ability to retain muscle mass and strength, it is believed that various forms of cancer treatment may be more effective, if only due to the fact that the cancer victim may be able to withstand the rigors of the various cancer treatments involved. There is presently, however, an absence of effective medical therapies to prevent or reverse skeletal muscle atrophy, and especially therapies that involve reliance on a modification of a patient's microbiome. Current treatment recommendations to address skeletal muscle atrophy (e.g. physical rehabilitation, nutritional optimization, and treatment of underlying disease) are often ineffective and/or unfeasible and at present, a pharmacologic therapy does not exist. Thus, a treatment for skeletal muscle atrophy associated with cancer represents a very large unmet medical need.
Cachexia is seen in the late stages of almost every major chronic illness, affecting 16-42% of people with heart failure, 30% of those with chronic obstructive pulmonary disease and up to 60% of people with kidney disease. Cachexia was overlooked for many years, with doctors directing their attention to the primary illness instead. Many, however, now view cachexia as a distinct, treatable condition. Basic research has revealed how it is driven by inflammation and metabolic imbalances. Treating cachexia may possibly give patients the strength to withstand chemotherapy or surgery. A key mechanism underlying cachexia is the increased breakdown of muscle protein, along with dampened protein synthesis, which leads to overall muscle loss. Certain genes are active in atrophying muscles, including genes encoding enzymes called E3 ubiquitin ligases, which tag proteins for destruction in the cell. Muscle cells seem to make more of these ligases when hit with certain inflammatory signals from tumors or from immune cells responding to cancer or other illness.
In the US, bladder cancer is the fourth most common type of cancer in men and the ninth most common cancer in women. Non-muscle invasive bladder cancer (NMIBC) begins and stays in the cells lining the bladder without growing into the deeper main muscle layer of the bladder, and accounts for the majority (70-80%) of patients diagnosed with bladder cancer. Bladder cancer has the highest recurrence rate of any malignancy. Although NMIBC is a relatively benign disease, it recurs in 50-70% of patients, of which 10-20% eventually progress to high-grade muscle-invasive disease. More than 1 million patients in the US and Europe are estimated to be affected by the disease.
The clinical management of bladder cancer has not changed significantly in several decades, with intravesical bacillus Calmette-Guérin immunotherapy being a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. Bacille Calmette-Guerin strains are currently used as commercial vaccines, with descendants of the original M. bovis isolate being passaged in vitro through hundreds of cycles. Following surgical treatment and depending on its stage, non-muscle invasive bladder cancer (NMIBC) can be controlled by immunotherapy using the Bacillus Calmette Guerin (BCG) vaccine instilled repeatedly in the bladder, usually as a six-week course followed by yearly maintenance therapy. The application of the BCG vaccine in this context is a first line therapy and generally regarded as the oldest and to date most successful immunotherapy of cancer. The anti-tumor effect of BCG is not fully understood, but involves infection of urothelial or bladder cancer cells and induction of both nonspecific inflammatory as well as specific anti-tumoral responses. NMIBC is typically treated with intravesicular BCG, which elicits a nonspecific local immune response against the tumor cells. BCG also elicits a nonspecific massive local inflammatory reaction in the bladder wall, and elevated appearance of cytokines can be detected in the urine of BCG-treated patients. BCG is internalized by antigen-presenting cells, such as macrophages, but also by urothelial tumor cells, which result in an altered gene expression of these cells.
The majority of tumors harbor p53 mutants. As the “guardian of the genome,” p53 is arguably one of the most important tumor suppressors that controls the regulation and expression of many genes that mediate cell cycle arrest, DNA repair and apoptosis. Under physiological conditions, newly synthesized p53 quickly undergoes ubiquitination and degradation. The p53 tumor suppressor protein plays critical roles in preventing malignant transformation by inducing cell growth arrest or apoptosis. Normally, p53 is inactive in the cell and its levels are low. In response to cellular stress such as DNA damage, p53 levels increase dramatically and it becomes activated through multiple post-translation modifications. Although the induction of p53 is partly due to its stabilization through interaction with the ubiquitin ligase MDM2, it is now clear that newly synthesized p53 also contributes to its accumulation. The induction of p53 following DNA damage is accompanied by increased association between eIF-4E, a protein translation initiator that binds to 5′-cap of eukaryotic mRNA, and its inhibitory protein 4E-BP1. This indicates a decrease in cap-dependent translation following DNA damage. An internal ribosomal entry site (IRES) at the 5′-untranslated region (UTR) of the p53 mRNA can recruit the 40S ribosomal subunit independent of the eIF-4E protein in response to DNA damage and other cellular stress. The presence of the IRES sequence is found in the p53 mRNA. It is believed that p53 down-regulates the activity of enablers such as FGF13.
Despite massive research efforts and the very impressive progress made over the past several decades, full molecular understanding of cancer and cachexia still remains a major challenge to the biomedical community. There exists a long felt but unsolved need for a simple, relatively inexpensive, effective treatment of muscle atrophy associated with a host of different types of cancer and other diseases. The present invention addresses this need in a manner heretofore unappreciated or at least unrecognized by those in the relevant art.